Alzheimer's disease (AD) is one of the most common dementia showing slowly progressive cognitive decline. Alzheimer's brain is characterized by accumulation of amyloid beta peptide (Aβ) and the formation of neurofibrillary tangles. AP plays a central role in the development of AD pathology and contributes to neuronal, synaptic, and cognitive malfunction. Mitochondrial and synaptic dysfunction is an early pathological feature of Alzheimer's disease brain (Du, et al. (2010) Proc. Natl. Acad. Sci. USA 107:18670; Du, et al. (2011) Antioxid. Redox Signal. doi:10.1089/ars.2011.4277; Chen, et al. (2010) J. Alzheimer's Dis. 20 Suppl 2: 5569; Caspersen, et al. (2005) FASEB J. 19:2040; Reddy, et al. (2008) Trends Mol. Med. 14:45; Lin & Beal (2006) Nat. Med. 12:1241). Studies have highlighted the significance of mitochondrial Aβ accumulation and synaptic mitochondrial dysfunction. Aβ progressively accumulates in synaptic mitochondria and impairs mitochondrial structure and function including membrane potential, membrane permeability transition pore, respiration, energy metabolism, oxidative stress, mitochondrial dynamics, and calcium homeostasis (Caspersen, et al. (2005) supra; Du, et al. (2008) Nat. Med. 14:1097; Manczak, et al. (2006) Hum. Mol. Genet. 15:1437; Lustbader, et al. (2004) Science 304:448; Devi, et al. (2006) J. Neurosci. 26:9057; Eckert, et al. (2008) Neurodegen. Dis. 5:157; Hauptmann, et al. (2009) Neurobiol. Aging 30:1574; Du, et al. (2011) Neurobiol. Aging 32:398; Yao, et al. (2009) Proc. Natl. Acad. Sci. USA 106:14670; Yao, et al. (2011) J. Neurosci. 31:2313; Manczak, et al. (2011) Hum. Mol. Genet. 20:2495; Wang, et al. (2008) Proc. Natl. Acad. Sci. USA 105:19318). Thus, strategies that suppress/attenuate Aβ-induced mitochondrial toxicity in addition to Aβ levels in the brain and improve cognitive function are critical for preventing and/or halting Alzheimer disease (AD). Development of Aβ inhibitors or blocking the Aβ production one approach for prevention and treatment of AD.
Potent γ-secretase inhibitors are available to eliminate Aβ production. Unfortunately, subchronic dosing of rodents with γ-secretase inhibitors has caused abnormalities in the gastrointestinal tract, thymus, and spleen. These abnormalities are mechanism-based toxicities that likely result from the inhibition of the cleavage of Notch by γ-secretase (Sato, et al. (2006) Biochemistry 45:8649). These γ-secretase-mediated toxicities raise the critical question of whether an acceptable therapeutic index can be found for γ-secretase inhibitors.
Amyloid binding alcohol dehydrogenase (ABAD), a mitochondrial enzyme, plays a critical role in mitochondrial dysfunction and in the pathogenesis of AD. This enzyme has attracted considerable interest because of its ability to interact with the Aβ. Importantly, interaction of ABAD with Aβ mediates mitochondrial and synaptic dysfunction (Lustbader, et al. (2004) supra). Antagonizing Aβ-ABAD interaction with the ABAD decoy peptide that encompasses the amino residues responsible for Aβ binding to ABAD protects against aberrant mitochondrial and neuronal function and improves learning memory in AD transgenic mice (Yao, et al. (2011) supra; Takuma, et al. (2005) FASEB J. 19:597). Furthermore, interception of Aβ-ABAD interaction also significantly reduces mitochondrial and cerebral Aβ accumulation (Yao, et al. (2011) supra). These data suggest that Aβ-ABAD interaction is a potential target of the drug development for treatment of AD.
Inhibitors of the Aβ-ABAD interaction have been developed. For example, Congo red provides 100% inhibition of Aβ binding, whereas thioflavin T exhibits ˜20%. However, Congo red exhibits a high level of toxicity and poor cell permeability (Xie, et al. (2006) Bioorg. Med. Chem. Lett. 16:4657). Therefore, fluorogenic and radiolabeled derivatives of Congo red and thioflavin T were analyzed. The derivatives did not, however, exhibit an increase in inhibitory activity compared to the parent compounds (Kim, et al. (2006) ACS Chem. Biol. 1:461-469). Benzothiazoles such as fentizole were also shown to exhibit inhibitory activity (Xie, et al. (2006) supra). In particular, AG18051 was identified as a potent inhibitor of ABAD (IC50 of 92 nM; Marques, et al. (2008) Bioorg. Med. Chem. 16:9511-9518).

However, these known inhibitors of Aβ-ABAD interaction have disadvantages including low solubility, inability to cross the blood brain barrier (BBB), high toxicity, and/or low cell permeability.